title: Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.
abstract: Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.
authors.affiliation: Department of Psychiatry, Townsend Family Laboratories, Brain Research Center, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.forename: Guiqiong
authors.initials: G
authors.lastname: He
authors.forename: Philip T T
authors.initials: PT
authors.lastname: Ly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fox
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shengcai
authors.initials: S
authors.lastname: Wei
authors.forename: Xiulian
authors.initials: X
authors.lastname: Sun
authors.forename: Chia-Hsiung
authors.initials: CH
authors.lastname: Chen
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D002460:Cell Line; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000927:Anticonvulsants; D053764:Presenilin-1; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases